Receptor protein tyrosine kinases (RPTKs) are enzymes which span the cell membrane and possess an extracellular ligand binding domain, a transmembrane domain, and a cytoplasmic (intracellular) tyrosine kinase domain (catalytic domain). The intracellular portion participates in cellular signal transduction by phosphorylating specific tyrosine residues in RPTK substrate proteins which in turn triggers other transduction events (signal propagation). As a result, tyrosine kinases influence a number of aspects of cellular responses, such as proliferation, growth, differentiation, migration, metabolism and programmed cell death (apoptosis). It has been shown that many of these tyrosine kinases are frequently mutated and/or aberrantly expressed in a number of human disease states such as, for example, breast cancer, gastrointestinal cancers (colon, rectal, and/or stomach cancers), leukemia, ovarian cancer, and pancreatic cancer.
Some examples of RPTKs that mediate various cellular responses associated with hyperproliferative disease states include c-erbB-2, c-met, tie-2, PDGRr, FGFr, and EGFR. As such, compounds that selectively inhibit or modulate the activity of one or more tyrosine kinases could provide significant therapeutic benefit in a variety of hyperproliferative disease states or disorders in mammals.
FAK (focal adhesion kinase) and JAK (Janus kinase), lck, src, abl or serine/threonine (e.g., cyclin dependent kinases) are examples of non-receptor (cytoplasmic) protein tyrosine kinases (NRPTKs). Initially, NRPTKs were identified in the context of cell growth and differentiation but subsequently the constitutive activation or abherrent expresion of NRPTKs has been found to be associated with disease states characterized by abnormal cell growth, in particular cancer, in mammals.
The Janus kinase family (JAKs) consists of 4 members: JAK1, JAK2, JAK3 and TYK2. This family of kinases signal downstream from cytokine and some growth factor receptors. For example, the STAT (signal transduction and transcription) family of transcription factors is the principal, but not exclusive, target for JAKs. Constitutive JAK/STAT signaling is thought to play a critical role in oncogenesis and the progression of many different types of tumors by promoting multiple mechanisms of tumor pathogenesis, including cell proliferation, anti-apoptotic signaling, angiogenesis and tumor immune evasion (Yu et al. 2004). Moreover, constitutively activated JAK/STAT signaling is found in many tumor types, but not in normal tissues (Yu et al. 2004; Benekli et al. 2003). The ability of the JAK/STAT pathway to mediate resistance to apoptosis is particularly important, as most anti-cancer drugs affect tumors by inducing apoptosis.
Focal adhesion kinase (FAK) is an evolutionarily conserved non-receptor tyrosine kinase localized at focal adhesions, sites of cellular contact with the ECM (extra-cellular matrix) that functions as a critical transducer of signaling from integrin receptors and multiple receptor tyrosine kinases, including EGF-R, HER2, IGF-R1, PDGF-R and VEGF-R2 and TIE-2 (Parsons, 2003; Han and McGonigal, 2007). The integrin-activated FAK forms a binary complex with Src which can phosphorylate other substrates and trigger multiple signaling pathways. Given the central role of FAK binding and phosphorylation in mediating signal transduction with multiple SH2- and SH3-domain effector proteins (Mitra et al. 2005), activated FAK plays a central role in mediating cell adhesion, migration, morphogenesis, proliferation and survival in normal and malignant cells (Mitra et al. 2005; McClean et al. 2005; and Kyu-Ho Han and McGonigal, 2007). In tumors, FAK activation mediates anchorage-independent cell survival, one of the hallmarks of cancer cells. Moreover, FAK over expression and activation appear to be associated with an enhanced invasive and metastatic phenotype and tumor angiogenesis in these malignancies (Owens et al, 1995, 1996; Tremblay et al, 1996; Kornberg et al, 1998; Mc Clean et al 2005; Kyu-Ho Han and McGonigal, 2007) and correlated with poor prognosis and shorter metastasis-free survival.